Tetrazolyl derivatives of naturally occurring prostaglandins

ABSTRACT

The 2-descarboxy-2-(tetrazol-5-yl)- omega pentanorprostaglandins and various intermediates employed in their preparation. The novel prostaglandins of this invention have been found to have activity profiles comparable to the parent prostaglandins, but exhibit a longer duration of action than the parent prostaglandins.

United States Patent [1 1 Hess et al.

[ Dec. 30, 1975 [54] TETRAZOLYL DERIVATIVES OF NATURALLY OCCURRING PROSTAGLANDINS [75] Inventors: Hans-Jurgen E. Hess, Old Lyme; Leonard J. Czuba, New London; Thomas K. Schaaf, Old Lyme, all of Conn.

[73] Assignee: Pfizer Inc., New York, NY.

[22] Filed: Aug. 27, 1974 [21] Appl. No.: 500,944

Related US. Application Data [60] Division of Ser. No. 335,586, Feb. 26, 1973, Pat. No. 3,883,513, which is a continuation-in-part of Ser. No. 177,102, Sept. 1, 1971, abandoned.

[52] US. Cl 260/308 D; 260/240 R; 260/240.1; 260/343.2 R; 260/343.3; 260/343.6;

D; 424/269 [51] Int. Cl. C07D 257/04 [58] Field of Search 260/308 D, 240 R [56] References Cited UNITED STATES PATENTS 3,736,335 5/1973 Wendler et al. 260/340.9

Primary ExaminerArthur P. Demers Attorney, Agent, or FirmC0nn0lly and Hutz [57] ABSTRACT 1 Claim, No Drawings TETRAVZOLYL DERIVATIVES: or NATURALLY OCCURRING PROSTAGLANDINS CROSS-REFERENCE TO RELATED APPLICATION 5 which exhibit diverse physiological effects. For in-- stance, the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al., Acta Physiol. Scand. 64:332-339, 1965 and Bergstrom, et al., Life Sci. 6:449-455, 1967). This relaxant effect on small blood vessels probably accounts for the fall in systemic arterial blood pressure (vasodepression) observed on intravenous injection of PGE and PGA (Weeks and King, Federation Proc.,.23:327, 1964; Bergstrom, et al.,

1965, op.cit.; Carlson, et al., Acta Med. Scand. 1832423-430, 1968; and Carlson, et al., Acta Physiol.

Scand. 752161-169, 1969).;Another well known physi- I ological action for PGE andPGE is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).

Another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. l GE is known to possess the ability to induce labor (Karim, et al., J. Obstet Gynaec. Brit. Cwlth.

77:200-210, 1970) and also to induce therapeutic 9 abortion (Bygdemon, et al., Contraception, 4, 293

(1971) and to be useful for control of fertility (Karim,

Contraception, 3, 1973 (1971). Patents have been obtained for several prostaglandins of the E and P series as inducers of labor in mammals (Belgian Patent No. 754,158 and West German Patent No. 2,034,641 and on PGF F and F for control of the reproductive cycle (South African Patent No. 69/6089).

Still other known physiological activities for PGE are in the inhibition of gastric acidsecretion (Shaw and Ramwell, In: Worcester ymp. on Prostaglandins, New York, Wiley, 1968, p. 55-64) and also of' platelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967 It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. A substantial body of evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by B-oxidation of the carboxylic acid side-chain and by oxidation of the' ISa-hydroxyl group (Anggard, et al.,

.Acta. Physiol. Scand., 81, 396 (1971) and references cited therein).

It was, of course, considered desirable to create analogs of the prostaglandins which would have physiolog ical activities equivalent to the natural compounds, but

0 wherein R is hydrogen or Z-tetrahydropyranyl; and R is hydrogernalkanoyl having from 1 to 5 carbon atoms,

'benzoyl, p-phenylbenzoyl, or ozor B-naphthoyl.

A final series of novel intermediates is represented by the formula:

DETAILED DESCRIPTION OF THE INVENTION For the first step in the preparation of the above named prostaglandin analogs, the appropriate hemiacetal precursor is caused to react with the disodium salt of a novel reagent, 4-(tetrazol-5-yl)butyltriphenylphosphonium bromide, in a molar ratio of from about 1:2 to 1:5. Such precursors are as follows:

2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B- (3a-( tetrahydropyran-Z-yloxy )-trans- 1 -octenl -y] )cyclopentl a-yl -acetaldehyde, 'y-hemiacetal for PGE PGA PGF a PGF p PGE PGA 13,14-dihydro-PGF a PGF, 5 PGE and-PGA 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2/3- (3B-lower alkyl-3a-(tetrahydropyran-2-yloxy)-trans-1- octen- 1 -yl)-cyc1opent-l a-yl]acetaldehyde, 'yhemiacetal for the 15-lower alkyl derivatives of these same prostaglandins;

2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B- (3a-(tetrahydropyran-2-yloxy)oct-1-yl)cyclopent-l ayllacetaldehyde, 'y-hemiacetal for 13,14-dihydro PGF a PGF B PGE and PGA 2[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy)- 2B('3B-lower alkyl-3a-(tetrahydropyran-2-yloxy)-oct- 1-yl]cyclopentl a-yl]acetaldehyde, 'y-hemiacetal for the l5-lower alkyl derivatives of 13,14-dihydro PGF a PGF B PGE and PGA 2-[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy)-2B- (3 B.-(tetrahydropyran-Z-yloxy )-trans- 1 -octen- I -yl)cyclopent-la-yl]acetaldehyde, 'y-hemiacetal for l5-epi- PGF PGF, PGA PGE IGF PGF PGE PGA 13?,14-dihydro-PGF a PC1 ,PG and PGA,;

2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2fl- (3a-lower alkyl-3B-(tetrahydropyran-2-yloxy)-transl octen-1-yl)-cyclopent-l a-yl]acetaldehyde, 'y-hem iacetal for the l5-epi-15-lower alkyl-PGF, a PGF PGA ,PGE PGF a PGF PGE PGA 13,94-

dihydro-FGF a PGF PGE and PGA,;

2-[5a-hydr0xy-3a-(tetrahydropyran-2-yloxy)-2B- (3B-(tetrahydropyran-Z-yloxy)oct-l-yl)cycl0pent-1ayl]acetaldehyde, 'y-hemiacetal for l5-epi-l3,l4-dihydro PGF a PGF PGE and PGA 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy-2B-(3alower alkyl-3B-(tetrahydropyran-2-yloxy)oct-1-yl)cyclopent-la-yl]acetaldehyde, 'y-hemiacetal for lS-epil5-lower alkyl-l 3,14-dihydro F'GF a PGF B PGE and PGA and 2-[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy)-2B- (3a-( tetrahydropyran-Z-yloxy )-cis-5 -trans-1-octadienl-yl)cyclopentla-yl]acetaldehyde, 'y-hemiacetal for PGF a POE- and PGA The reaction will preferably be carried out at temperatures of about 25-65C. in an inert solvent such as dimethylsulfoxide and in an inert atmosphere, for a period of up to about 4 hours or until the reaction is essentially complete.

The tetrazol-containing intermediates produced in the first step, as described above, may be converted by published procedures (Corey, et al., J. Am. Chem. Soc., 93, 1490 (1971) to the tetrazoyl analogs of any of the prostaglandins listed above. These procedures are further described in detail in the appended examples and the steps entailed are summarized in the flow sheet below.

REACTION SCHEME A THPd H OIHP PGF PGF and- PGAQ tetrazoyl and tetrazoyl 15, lh-dihydro PGFm, tetrazoyl Per PGE m REACTION SCHEME B N- N (i PCI-I (CH C I Na VI II 13 lh-dih dro PGiQa, PGF PGE2, PGA

' VII As shown in Reaction Scheme A, Hemiacetal I is caused to react with the novel reagent II to produce III, the tetrazoyl analog of the bis-THP ether of PGF a III PGF a -tetrazoyl involves hydrolysis with aqueous acetic acid, concentration, and purification by column chromatography.

III PGE -tetrazoyl requires treatment with Jones reagent to form a second intermediate before the acid treatment and purification as above.

PGF B -tetrazoyl is obtained by treating PGE -tetrazoyl with sodium borohydride, hydrolysis, concentration, and purification by column chromatography.

PGA -tetrazoyl is obtained by treating PGE -tetrazoyl with formic acid, concentration, and purification by column chromatography.

III PGF -tetrazoyl requires a reduction with palladium on carbon and methanol to produce IV which may then be hydrolysed with aqueous acetic acid, and purified as above.

III PGE -tetrazoyl PGF -tetrazoyl follows exactly the same method as outlined for the PGE PGF B series above.

III PGE -tetrazoyl PGA -tetrazoyl follows exactly the same method as outlined for the PGE PGA series above.

III I3,l4-dihydro PGF requires a reduction with palladium on carbon. and methanol to produce V which is then hydrolysed with aqueous acetic acid, and purified as above. To produce the other 13,14-dihydro derivatives one follows the procedures outlined above.

Referring now to Reaction Scheme B, Hemiacetal VI 'is caused to react with the novel reagent II to produce VII, the tetrazoyl analog of the bis-THP ether of 13,14-

dihydro PGF a VII 13,14-dihydro PGF a -tetrazoyl involves hydrolysis with aqueous acetic acid, concentration, and

purification by column chromatography.

ves, or IS-epimeric-lS-lower alkyl derivatives of all of the above mentioned prostaglandin tetrazoyls, one merely employs hemiacetal VIII XIII, and proceeds as aboveto produce the desired compound.

To produce the lS-epimeric, l5-lower alkyl deriva-.

To produce PGF PGE and PGA tetrazoyl, hemiacetal XIV is employed as the starting material and all of the other reaction steps are identical to those given above.

XIV

OTHP

XIII

trans-l-octen-l -yl)cyc1opent-la-yl]acetaldehyde, y-

hemiacetal for l5-lower alkyl-PGF PGF and 2-[3a,5a-dihydroxy-2B-((3a-lower alkyl-3B-hydroxy-trans-1-octenlyl)cyclopent-1a-yl1acetaldehyde, y-hemiacetal for l5-epi'l5-lower alky1PGF2a, PGF and l3,l4-dihydro PGF 2-[3a,5a-dihydroxy-2B-(3ahydroxyoct-1-yl)cyclopent-la-yl]acetaldehyde, y-hemiacetal for l3,l4-dihydro PGF 2-[3a,5a-dihydroxy-2B-( 3B-hydroxyoctl -yl )cyclopent-la-yl1acetaldehyde, 'y-hemiacetal for lS-epil3,l4-dihydro PGF 2-[3a,5a-dihydroxy-2B-(3B-lower alkyl-3a-hydroxyoct- 1 -yl)-cyclopentl a-yl]acetaldehyde, 'y-hemiacetal for l5-lower alkyl-l3,l4-dihydro PGF 2-[3a, Sa-dihydroxy-2B-(3a-1ower alkyl-3B-hydroxyoct- 1 -yl )-cyclopent-la-yl ]aceta1dehyde, 'y-hemiacetal for IS-epi-lS-lower alkyl-l3,l4-dihydro PGF The reaction will preferably be carried out at temper.- atures of about 25-65 in a solvent such a dimethylsulfoxide, and under an inert atmosphere, for a period of up to 4 hours until the reaction is essentially complete. Dilution with water, acidification extraction, concentration, and purification by column chromatography affords the PGF tetrazoyl analogs.

The PGF PGF PGE and PGA, tetrazoyl and analogs may be prepared by the alternate synthesis summarized in flow sheet C. For the first step in the preparation of the above named prostaglandin analogs, the hemiacetal 2-[5a-hydroxy-3a-(tetrahydropyran-2- yloxy )-2B-benzyloxymethyl cyclopent-la-yl]-acetalde- REACTION SCHEME C As shown in Reaction Scheme C, hemiacetal XV is caused to react with the novel reagent ll to produce XVI.

XVI XVII involves treatment with acetic anhydride and pyridine to form a second intermediate, re-

duction with hydrogen and palladium on carbon in acetic acidzethanol to form a third intermediate, and oxidation with Collins reagent.

PGE PGF PGF PGA tetrazoyl XVII IV requires treatment with the sodium salt of dimethyl 2-oxoheptylphosphonate to form a second intermediate, reduction with lithium tris-sec-butylborohydride to form a third intermediate, treatment with dihydropyran to form a fourth intermediate, and treatment with aqueous sodium hydroxide.

IV PGE PGF PGF and PGA tetrazoyl one follows the procedure out med above.

The tetrazoyl analogs described above may be transformed into other types of derivatives. For example, treatment of PGE -tetrazoyl with an ethereal solution of diazomethane followed by concentration and column chromatography provides both the PGE l-N- methyltetrazoyl and the PGE 3-N-methyltetrazoyl. Furthermore, the 9,1 l,l5-triesters of the PGF-tetrazoyls or the ll,l5-bis esters of the PGE-tetrazoyls may be prepared by treatment of the parent compound with the appropriate acid chloride or acid anhydride in the presence of a base such as pyridine. These procedures are further described in detail in the appended examples.

Lower side-chain modified prostaglandin tetrazoyls, i.e. bis-w-homo PGF- tetrazoyl or l6,l6-dimethyl PGE tetrazoyl, may be prepared starting with the appropriately substituted hemiacetal and the several procedures described above. These procedures are further elaborated in detail in the appended examples.

As the literature cited under Background of the Invention establishes, the natural prostaglandins are known to exhibit a spectrum of physiological activities.

To examplify the greater tissue selectivity of the tetrazoyl derivatives, the threshold dose for spasmogenic effect on isolated smooth muscle from rabbit aorta, was found to be 250 ng/ml for PGE and 500 ng/ml for PGE -tetrazoyl. In this same test using guinea pig ileum, values of ng/ml and 100 ng/ml were obtained for the same two compounds.

In the test for effects on dog blood pressure, both PGE and PGE -tetrazoyl were found to be depressors and values of 0.16 ug/kg and 0.8 pg/kg were obtained on the two compounds as the threshold dose for this effect.

In contrast, in the test for protection by 100 ug/ml of the test compound against histamine induced bronchospasm in guinea pigs, values of 65-75% were obtained for both PGE and PGE tetrazoyl. Thus, PGE -tetrazoyl appears to be a more tissue selective bronchodilator than PGE That the duration of the action of the lSB-lower alkyl tetrazoyl analogs is increased over that of the parent prostaglandin is clearly illustrated by the data in Table I below. This experiment demonstrates that a comparable drop in the blood pressure of anesthetized dogs were achieved with a comparable i.v. administered dose of the natural prostaglandin PGE, or its tetrazoyl analog. In the case of the l5-methyl PGE tetrazoyl analog, while the size of the dose must be increased to achieve an equivalent drop in blood pressure, the length of time that this reduced pressure is maintained is increased dramatically.

TABLE I Dog No. Compound Used Dose Recovery ug/kg IV Pre Post mm Hg Time Min.

1 PGE, 4 I38 l 10 28 PGE -Tetrazoyl 4 138 1 10 28 3 l lS-Methyl-PGE,- 50 135 108 27 37 Tetrazoyl 2 PGE; 2 130 92 38 4 PGE -Tetrazoyl 2 I25 95 6 IS-Methyl-PGE 50 128 93 26 Tetrazoyl 3 PGE, 2 H5 92 23 6 PGE -Tetrazoyl 2 I I4 90 24 l O lS-Methyl-PGE 1 I4 24 120 Tetrazoyl 4 PGE, 2 I30 [00 30 6 PGE -Tetrazoyl 2 132 l 10 22 6 IS-MethyI-PGE 50 136 103 33 30 Tetrazoyl 5 PGE 2 82 33 5 PGE -Tetrazoyl 2 l 10 9O 30 8 l S-Methyl-PGE S0 92 28 40 Tetrazoyl Blood pressure before administration of drug. Blood pressure after administration of drug.

In numerous in vivo and in vitro tests we have demonstrated that the tetrazoyl prostaglandin analogs possess the same physiological activities as the natural prostaglandins with greater selectivity of action. These tests include, among others, a test for effect on isolated smooth muscle from rabbit aorta and guinea pig ileum, a test for inhibition of norepinephrine induced lipolysis in isolated rat fat cells, a test for effect on histamine and induced bronchospasm in guinea pig, a test for effects on dog blood pressure, and a test for effects on rat blood pressure.

The new compounds of this invention can be used in a variety of pharmaceutical preparations and they may be administered by a variety of routes, such as intravenous, oral and topical including aerosol, intravaginal, and intranasal among others, The dosage amounts and dosage routes for the new compounds of the invention generally are equivalent to those of the corresponding natural prostaglandins for the selected utility. This is verified by the following exemplary dosage forms and amounts illustrated below for specific compounds.

The natural prostaglandins of the E and F series are well known agents for the induction of abortion, and the corresponding tetrazoyl prostaglandins share this utility. For such treatment an aqueous suspension of PGE or PGF -tetrazoyl is appropriately administered at a level of from about 0.2-5.0 mg/dose for PGE -tetrazoyl or 3.0-50 mg/ dose for PGF -tetraz oyl with from 1 to 7 oral doses per day being employed in either case.

If an intravaginal treatment for abortion induction is desired, a suitable agent is a sterile ethanolic solution of either of these two tetrazoyl prostaglandins or lactose tablets of the same two agents. In such treatments suitable doses are from 15-200 mg/dose for PGE -tetrazoyl or from 35-250 mg/dose for PGF -tetrazoyl with 1 or 2 doses being employed.

In cases where a midterm abortion is necessary, an effective agent is an ethanol-dextrose solution of PGE tetrazoyl administered as an intravenous infusion. A suitable dosage is from about 5-500 Lg/min adminis tered for a period of from 1-24 hours.

If an intra-amniotic treatment for midterm abortion is necessary, an effective agent is a sterile ethanolic solution of either PGE or PGF -tetrazoyl administered directly into the amniotic sac by means of a polyethylene catheter. A suitable dose is from 0.5-5.0 mg/dose for PGE -tetrazoyl or 5-50 mg/dose for PGF -tetrazoyl with from 1 to 5 doses administered.

Another use for the tetrazoyl prostaglandins is as an inducer of labor. For this purpose an ethanol-saline solution of PGE tetrazoyl is employed as an intervenous infusion in the amount of from about 3-100 ug/kg/min for from 1-10 hours.

Still other applications for the E-series prostaglandintetra are to produce bronchodilation or to increase nasal patency. An appropriate dosage form for this use is anaqueous ethanolic solution of PGE or PGE -tetrazoyl which for bronchodilator use is employed as an aerosol using fluorinated hydrocarbons as propellant in the amount of from about 3-500 ug/dose.

A use for A- series tetrazoyl prostaglandins is as antihypertensive agents. For such a treatment an ethanol solution of PGA or PGA -tetrazoyl is appropriately administered as an intravenous infusion at about 1-30 pg/kg/min for a total dose of from 1-20 mg/kg/day.

The utility and dosage amounts of the -lower alkyl substituted tetrazoyl prostaglandins generally parallels that of the l5-desalkyl derivatives.

It will be seen that the formulae appearing in the foregoing depict optically active compounds. It will be clear, however, that the corresponding racemates will exhibit valuable biological activity by virtue of their content of the above-mentioned biologically active optical isomer, and it is intended that such racemates also be embraced by the foregoing formulae herein and in the appended claims. The racemic mixtures are readily prepared by the same methods employed herein to synthesize the optically active species, by mere substitution of corresponding racemic precursors in place of optically active starting materials.

The following examples are merely illustrative, and in no way limit the scope of the appended claims. All temperaturesare given in degrees Centigrade and all percentages are by weight.

EXAMPLE I A mixture of 5-bromovaleronitrile (16.2 g., 0.10 mole), triphenylphosphine (26.2 g., 0.10 mole) and toluene ml.) was heated to reflux with stirring under nitrogen for 16 hours. The resulting thick white suspension was cooled to room temperature and filtered. The residue was washed with benzene and air dried to give 33.0 g. of a white, crystalline solid, mp. 230-'232, which was 4-cyanobutyltriphenylphosphonium bromide.

Anal. Calcd for C 1-i BrNP: C, 65.10; H, 5.47; N, 3.30. Found: C, 65.01; H, 5.40; N, 3.19.

A mixture of the phosphonium salt above (10.0 g., 23.5 mmoles), ammonium chloride (1.60 g., 30.0 mmoles), lithium chloride (0.032 g., 0.76 mmole), sodium azide (1.91 g., 29.3 mmoles), and dimethylformamide (50 ml.) was heated to 127 (oil bath) under nitrogen with stirring for 18 hours. The resulting suspension was cooled and filtered. The residue was washed with dimethylformamide and the combined filtrate and washings were concentrated (aspirator pressure, ca. 45). The oily residue was crystallized from water at 0 and air dried to give a white crystalline solid (8.11 g.), m.p. 100-102. The product was recrystallized from methanol-ether to give white prisms (7.18 g.), m.p. l97-206. An analytical sample was prepared by recrystallization from 2-propanol to give a white crystalline powder, m.p. 2l2-2l3, which was- 4-(tetrazol-5-yl)butyltriphenylphosphonium bromide.

Anal. Calcd for C 1-1 H Pl3r: C, 59.10; H, 5.17; N, 11.99; 11 6.63; Br, 17.09.Found: C, 59.35; H, 5.28; N, 12.31; P, 6.78; Br, 17.26.

EXAMPLE 11 Sodium hydride mineral oil dispersion (56.6%, 2.12 g., 1.20 g. dry powder) was washed with three portions of pentane under dry nitrogen. The resulting gray powder was stirred with dry dimethylsulfoxide (25 ml., distilled from Cal-l bp ca. 60 at 6 mm) under nitrogen at 60-65 for 2 hours to give a cloudy, gray solution. The solution was cooled, and an aliquot was diluted with water and was titrated to a phenolphthalien end point with 0.100N hydrochloric acid to determine a molarity of 2.07. A portion of the standardized solution (5.36 ml., 1 1.1 mmoles) was added dropwise ovega 15 min. period to a stirred solution of the final phosphonium salt of Example I (2.70 g., 5.78 mmoles) in dry dimethylsulfoxide (8 ml.) under nitrogen at room temperature. To the resulting red solution was added a solution of 2-[5a-hydroxy3a-(tetrahydropyran-2-yloxy)-2B-( 3a-tetrahydropyran-2-yloxy)-transl -octen-1 -ylcyclopent-la-yHaCetaldehyde, y-hemiacetal [known compound, see E. J. Corey, et al. ,J'. Am Chem. S0c.,92, 397 (1970), 1.00 g., 2.28 mmoles] in dimethylsulfoxide (6 ml.) over a 50 min. period while stirring the mixture under nitrogen at room temperature. The mixture was stirred for an additional 2% hours and then was poured into ice-water (100 ml.). The aqueous mixture was acidified with 1.0N hydrochloric acid (11.8 ml.) and extracted with three 50 ml. portions of ethyl acetate. The extract was washed with water (20 ml.), dried (MgSO and concentrated (aspirator pressure, ca. 40) to give a red oil (2.51 g.). The crude oil was chromatographed on 60-200 mesh silica gel (50 g.) using chloroform, ethyl acetate and methanol as successive eluents to separate a mixture containing mostly triphenylphosphine oxide (10.5 g.). unchanged starting material (0.18 g., 18% recovery), the expected product, 3B-[3a-(tetrahydropyran-Z-yloxy)-trans- 1octen-1yl]-2a-[6-(tetrazol-5 yl )-cis-2-hexenl yl]- 4a-(tetrahydropyran-2-yloxy)-cyclopentan-104-01 as a thick colorless oil (0.690 g. 50.5% yield), and a mixture of expected product and unidentified products (0.459 g.). The fractions were identified by thin layer chromatography on neutral silica gel glass plates using ethyl acetate or chloroform-methanol (5:1 as developer and the chromatographs were visualized by heating with a vanillin-phosphoric acid reagent. The expected product exhibited R, values of 0.22 and 0.72, respectively, with these two developing systems. This compound is an important intermediate in the synthesis of tetrazoyl analogs of several prostaglandins, as is illustrated below.

EXAMPLE III A mixture of the bis Tl-IP ether of Example 11 (333 mg., 0.614 mmoles), acetic acid (6.5 ml.) and water (3.5 ml.) was stirred under nitrogen for 4 hours at 4045. The resulting clear solution was concentrated (aspirator pressure, ca. 40) and the residue (335 mg.) was partitioned between water (20 ml.) and ethyl acetate (20 ml.). The ethyl acetate layer was separated and combined with an ethyl acetate extract (20 ml.) of the aqueous layer. The combined ethyl acetate solutions were washed with brine (20 ml.), dried (Na SO and concentrated (aspirator pressure ca. 40) leaving a clear, faintly tan oil (223 mg.). The oil was chromatographed on acidic silica gel g., Malinckrodt Silicar CC-4, 100-200 mesh) using chloroform followed by mixtures of chloroform and methanol as eluents to separate an unidentified mixture (87 mg.) and the desired product, 3B(3a-hydroxy-trans-1-octen-lyl)-2a -[6-(tetrazol-5yl)-cis-2-hexen-1-y1]-cyclopentan-1a,- 4a-diol, as a thick colorless oil (103 mg., yield 44%). Thin layer chromatograph of product on silica gel glass plates using chloroform-methanol (5:1) as the developer and visualizing the chromatogram by heating with vanillin-phosphoric acid reagent showed a single spot at R, 0.13. This product is 2-descarboxy-2-(tetrazol- 5-yl) PGF The above product may be hydrogenated as described in Example VA to provide 3B-(3a-hydroxyoctlyl )-2a-[6-(tetrazol15-yl )hexl -yl]cyclopentan- 1 (1,40:- diol.

EXAMPLE IA To a solution of the 4-(tetrazol-5-yl)butyltriphenylphosphonium bromide prepared in Example I (4.65 g.; 10.0 m moles) in 50 ml. of dry tetrahydrofuran is added a solution of diazomethane in ether until the reaction solution remains yellow for 5 minutes. Concentrations followed by chromatographic purification affords the desired 4-(1N-methyltetrazol-S-yl)butyltriphenylphosphonium bromide and 4-(3-N-methyltetrazol-5- yl)butyltriphenylphosphonium bromide.

These compounds may be converted by methods both known (see: E. J. Corey, et al., J. Am. Chem. Soc, 92, 397 (1970) and described herein to the 2-descarboxy-2-( l N-methyltetrazol-S-yl) and 2-descarboxy-2- (3-N-methyltetrazol-5 -yl )prostaglandins.

EXAMPLE IV To a stirred solution of the bis THP ether of Example II (400 mg., 0.731 mmoles) in acetone (12.3 ml.) at 10 was added, dropwise over a 5 minute period, 0.29 ml. of Jones reagent previously prepared from 2.67 g. chromium trioxide and 2.3 ml. concentrated sulfuric acid diluted to 10 ml. volume with water. The resulting mixture was aged for 15 minutes at -10 and then treated with isopropyl alcohol (0.46 ml.). The mixture was stirred for an additional 5 minutes at 10 and partitioned between ethyl acetate (30 ml.) and water (30 ml.). The ethyl acetate layer was separated and combined with an ethyl acetate extract of the aqueous layer. The combined solutions were washed with three l5-ml. portions of water, dried (MgsQr), and concentrated (aspirator pressure, ca. 4050) leaving 358 mg.

of 4a-tetrahydropyran2-yloxy)-3B[ 3a-(tetrahydropy ran-2-yloxy)-trans- 1octen-l-yl] -2a-[6-(tetrazol-5-yl)- cis-2-hexen-lyl]cyclopentanone as a viscous oil.

EXAMPLE V The oil produced in Example IV was stirred with acetic acid (10.7 ml.) and water (5.8 ml.) under nitrogen at 4045 for 3 hours. The resulting solution was concentrated (aspirator pressure, ca. 4050) and the residue (275 mg.) was chromatographed on acidicsilica gel (25 g. Malinckrodt Silicar CC-4, -200 mesh) using mixtures of chloroform and methanol as the eluent to separate an unidentified mixture mg.) and the desired product, 4a-hydroxy-3fi-(3ahydroxy-transl octenl -yl)-2a-[6-(tetrazol-5-yl)-cis- 2-hexen-1-yl]cyclopentanone, as a clear, thick, colorless oil (103 mg., 37%). Thin layer chromatography of the product on silica gel glass plates using methylene chloridemethanol (9:1) or benzene-tetrahydrofuranformic acid (15512) as the developers and visualizing the chromatograms by heating with vanillin-phosphoric acid reagent showed a single spot with R, values of 0.30 and 0.25 on the two systems, respectively. The ir spectrum (CI-ICl of the product exhibited a strong absorption band at 1730 cm (C=O) and a moderately weak band at 3610 cm (OH). The uv spectrum (95% EtOl-l) of the product showed only end absorption. This product is 2-descarboxy-2-(tetrazol-5-yl)PGE Treatment of a small sample of the product with 10 aqueous sodium hydroxide and ethanol for 15 minutes at room temperature gave a single product by tlc (R, 0.38, silica gel, benzene-tetrahydrofuran-formic acid, 15522). The uv spectrum (95% EtOH) of the latter product exhibited an absorption maximum at 279 my. 19,600).

EXAMPLE VA A heterogeneous mixture of the product of Example V (147 mg; 0.390 mmole) and 45 mg. of 5% palladium on carbon in 20 ml. of absolute methanol was stirred under 1 atmosphere of hydrogen for 2.0 hours at room temperature. The reaction was then filtered through a pad of Celite and concentrated. Purification of the crude product by silica gel chromatography (Mallinck- 17 rodt CC-4) using mixtures of methanol in chloroform as eluents afforded the desired 4a-hydroxy-3B-(3ahydroxyoct--1-yl)-2a-[6-(tetrazol-5 yl )hexl -yl] cyclopentanone as a colorless oil weighing 47 mg.

The mass spectrum of the product exhibited a peak at mle 362 for M-I-I O. The ir spectrum of the product exhibited a strong absorption at 1740 cm for the ketone carbonyl and no absorption at 970 cm for the trans olefin.

EXAMPLE VB A heterogeneous mixture of 148 mg. (0.400 mmole) of the product of Example V and 45 mg. of 5% palladium on carbon in 15 ml. of absolute methanol was stirred under '1 atmosphere at for 2.0 hours (one equivalent of hydrogen was consumed). The reaction was then filtered through a pad of Celite and concentrated. Purification of the crude product using mixtures of methanol in ethyl acetate afforded the desired 4ahydroxy-3B-( 3a-hydroxy-trans- 1 octenl yl )-2a-] 6- (tetrazol--yl)hex-l-yl]-cyclopentanone as a viscous, colorless oil weighing 22 mg.

The nmr spectrum (CD OD) of the product exhibited a multiplet at 5.72-5.51 8 for the trans olefin, a multiplet at 4.19-3.80 8 for the C110, a triplet at 2.93 8 (J 7 cps) for the CI;I -tet, and multiplets at 2.76-0.60 6 for the remaining protons.

This prostaglandin analog may be converted by the process of Example IX to 2-descarboxy-2-(tetrazol-S- yl)PGA and by the process of Example XXIII to 2- descarboxy-Z-(tetrazol-S-yl)PGF EXAMPLE VI A mixture of the bis TI-IP ether produced in Example 11 (198 mg.), a 5% palladoium on carbon (200 mg.) and methanol ml.) was stirred under one atmosphere of hydrogen for 65 hours at room temperature.

The mixture was filtered and the filtrate was concentrated (aspirator pressure, ca. 40) to give 132 mg. of a thick, colorless oil 3B-[3a-(tetrahydrOpyran-Zyloxy )oct- 1 yl 2a- 6-( tetrazol-S -yl)-hex-1yl)-hex-l-yl]-4a- (tetrahydropyran-Z-yloxy)cyclopentan- 1 04-01. The thinl layer chromatogram of the product showed asingle spot: which was not distinguishable from that of the starting material (from Example II) as described above. The product was identified by a hydrolysis experiment in which the Rf of the hydrolysedproduct was found to be 0.20 while the R, of the hydrolysis product of the starting material was 0.13.

EXAMPLE VII A sample of the product of Example VI (21 mg.) was hydrolyzed with acetic acid (0.5 ml.) and water (0.3 ml.) and then purified as described in Example III to give pure 3B-(3a-hydroxyoct-l-yl)- 2a-[6-(tetrazol-5 -yl)hex l yl]cyclopentane- 1 01,411- diol as a thick, colorless oil (8 mg.).

Thin layer chromatography of the product on silica gel glass plates developed with benzene-tetrahydrofuran-formic acid (:5:2) exhibited a single spot (vanillin-phosphoric acid indicator) with an R, of 0.20. This product is 2-descarboxy-2-(tetrazol-5-yl)-13,14-dihydro PGF EXAMPLE VIII The product of Example VI (131 mg.)'was oxidized with Jones reagent (0.094 ml.) as described above in Example V. Isolation of the product and subsequent hydrolysis yielded the pure product 4a-hydroxy-3B- 18 (3a-hydroxyoct-lyl)-2a-[6-(tetrazol-5-yl)hex-lyl]cyclopentanone as a thick, clear, colorless oil (49 mg.). Thin layer chromatography of the product on silica gel glass plates developed with methylene chloride-methanol (9:1) showed a single spot (vanillinphosphoric acid indicator) with an R, 0.31. The infrared spectrum (CHCl of the product showed a strong absorption band at 1730 cm (C=O) and a moderately weak band at 3610 cm (OI-I). This product is 2- descarboxy-Z-(tetrazol-S-yl)-13,14-dihydro PGE The uv spectrum EtOI-I) of the product exhibited only end absorption, and treatment of the uv spectrum sample with 40% potassium hydroxide did not form a product(s) with significant absorption maxima in the 220-300 mp. region of the spectrum.

This prostaglandin analog may be converted by the process of Example IX to 4B(3a-hydroxyoct-1yl)-5a- [6-(tetrazol-5-yl)hex-1-yl]cyclopent-2-en-l-one, 2- descarboxy-2-(tetrazol-5-yl)-13,14 dihydro PGA and by the process of Example XXIII to 2-descarboxy-2- (tetrazol-S -yl)-1 3,14-dihydro PGF EXAMPLE IX The product of Example V (45 mg.) was stirred with 97% formic acid (0.18 ml.) for 2% hours. The resulting mixture was diluted with ice-water (ca. 4 ml.). The aqueous mixture was extracted with three 5-ml. portions of ethyl acetate. The extract was dried (Na SO and concentrated (aspirator pressure, ca. 40-50) to give a crude oil (39 mg. Chromatography of the crude product on acidic silica gel (4 g., Malinckrodt CC-4, 100-200 mesh) using mixtures of chloroform and methanol as the eluent to separate the desired product 4B-( 3a-hydroxy-trans-l -octen-1-yl)-5 a- 6-( tetrazol-S yl)-cis-2-hexen-l-yl]cyclopent-2-en-lone, as a thick, colorless oil (10 mg.) and an unidentified product (17 mg.). Thin layer chromatography of the product on silica gel glass plates developed with benzene-tetrahydrofuran-formic acid (15:5:2) showed a single spot (vanillin-phosphoric acid indicator) with an R, 0.50. The infrared spectrum (CI-ICl of the product showed a strong absorption band at 1710 cm (conjugated C=O in a five-membered ring) and a moderately weak band at 3610 cm (OH). The uv spectrum (95% EtOI-I) of the product exhibited an absorption maximum at 222 mp. This product is 2-descarboxy-2-(tetrazol-S-yl) PGA EXAMPLE X To a solution cooled to 78 of 2.68 g. (6.00 mmoles) of 2-[3a-p-biphenylcarboxy-5a-hydroxy-ZB- [3-oxo-transl octen- 1 -yl]cyclopentl a-yl]acetic acid, 'y-lactone, a known compound (see reference for Example II), in 26 ml. of anhydrous ether (Mallinckrodt) and 20 ml. of tetrahydrofuran (distilled from lithium aluminum hydride) was added dropwise 6.5 ml. (6.00 mmoles) of a 0.92 N solution of methyllithium in ether (Alfa). After being stirred at 78 for 15 minutes the reaction was quenched by the dropwise addition of glacial acetic acid until the pH of the reaction was approximately 7. The mixture was then diluted with methylene chloride and the diluted organic solution was washed with water (1X) and with saturated brine (1X), was dried (anhydrous magnesium sulfate) and was concentrated to afford 2.71 g. of the viscous, oily epimeric alcohols (97.8% yield).

The crude product was purified by column chromatography on 108 g. of silica gel (Baker Analyzed Reagent 60-200 mesh) using a mixture of benzenezethyl acetate as eluent. After elution of higher R, impurities, the desired ISu-hydroxy-ISB-methyl epimer, 2-[3a-pbiphenylcarboxy-Sa-hydroxy-2B-[ 3a-hydroxy-3B- methyl-trans-l-octen-l-yl]cyclopent-1a-yl]acetic acid, y-lactone was eluted weighing 0.853 g. (30.8% yield). Thin layer chromatography of the product on silica gel glass plates using a 10:1 mixture of etherz2-butanone as eluent showed a single spot having an R 0.45.

The ir spectrum (CI-ICl of the product exhibited strong absorptions at 1710 cm for the ester carbonyl and 1770 cm for the lactone carbonyl. The nmr spectrum (CDCl of the product showed a multiplet at 7.28-8.22 8 for the aromatic protons, a multiplet at 5.56-5.77 6 for the olefinic protons, a multiplet at 4.90-5.45 8 for the CI -IOCO, a singlet at 1.27 8 (C ll and multiplets at 0.57-3.10 8 for the remaining protons.

The above product may be reduced according to the procedure of Example XXXII to provide 2-[2B-(3B- methyl-3a-hydroxy-transl octenl -yl)-3a,5a-dihydroxycyclopentl a-yl]acetaldehyde, 'y-hemiacetal. This compound may be converted according to the procedure of Example XXXIII to l-methyl-2-descarboxy-2-(tetrazol-5-yl)PGF EXAMPLE XI A heterogeneous mixture of 1.30 g. (2.81 mmoles) of the chromatographed ester of Example X, 25 ml. of methanol, and 0.388 g. (2.81 mmoles) finely powdered anhydrous potassium carbonate was stirred under nitrogen for 2.0 hours at room temperature then was cooled in ice. To the cooled solution was added 5.60 ml. (5.60 mmoles) of 1.0 N hydrochloric acid. The cold, acidified solution was stirred for minutes then was diluted with 25 ml. of saturated brine. After filtration of the resultant solids the filtrate was extracted with ethyl acetate (3X). The combined ethyl acetate extracts were washed with water (1X), were dried (anhydrous magnesium sulfate), and were concentrated to afford 0.744 g. (94.0% yield) of a yellow, oily diol, 2-[ 3a,5a-dihydroxy-2B-( 3a-hydroxy-3 B-methyl-transl-octen-l-yl)cyclopent-l a-yl]acetic acid, 'y-lactone.

This oil was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using a 1:1 mixture of methylene chloride: ethyl acetate as eluent. After elution of higher R, impurities 0.507 g. of the desired diol was collected (64.0% yield). Thin layer chromatography of the diol product on silica gel glass plates using a 9:1 mixture of methylene chloride methanol as eluent showed a single spot having an R 0.65.

The ir spectrum (Cl-ICl of the diol exhibited a EXAMPLE XII To a solution, cooled in ice, of 0.507 g. (1.80 mmole) of the chromatographed diol of Example XI in 5.4 ml. of methylene chloride was added 0.54 ml. of dihydropyran (distilled from lithium aluminum hydride), and 18 mg. of p-toluenesulfonic acid monohydrate. The solution was stirred in the cold for 15 minutes then was diluted with ether. The organic solution was washed with saturated sodium bicarbonate (1X), was dried (anhydrous magnesium sulfate), and was concentrated to afford 0.870 g. (107% yield) of the pale-yellow, oily bis-THP ether 2-[5a-hydroxy-3a-(tetrahydropyran-Z- yloxy )-2B-( 3 B-methyl-3 a-( tetrahydropyran-Z-yloxy trans-1-octen-1-yl)cyclopent-la-yl]acetic acid, 'y-lactone, which was used without further purification. Thin layer chromatography of the oily product on silica gel glass plates using 5% methanol in methylene chloride as eluent showed a single spot having an R 0.85. The structure of the product was substantiated by the virtual identity of its ir spectrum with that of theknown l5-normethyl compound (see reference for Example II).

The above product may be hydrogenated according to the procedure of Example VA to provide 2-[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy)-2B-(3B- methyl-3a-(tetrahydropyran-Z-yloxy)octl -yl )cyclopent-1a-yl]acetic acid, 'y-lactone.

This product may be reduced according to the procedure of Example XIII to afford 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B-(3B-methyl;3a-(tetrahydropyran-2-yloxy )octl yl )cyclopentl a-yl acetaldehyde 'y-hemiacetal, a compound necessary for the preparation of 15-methyl-2-descarboxy-2-(tetrazol-5-yl)- 13,14-dihydro PGF PGF PGE and PGA EXAMPLE XIII To a solution cooled to 78 of 0.810 g. (1.80 mmoles) of the crude bis-Tl-IP ether lactone of Example XII in toluene was added 2.3 ml. (1.85 mmoles) of a 0.805 M solution of diisobutylaluminum hydride in hexane (Alfa). The solution was stirred at 78 for 15 minutes then was quenched by the dropwise addition of methanol until gas evolution ceased. The quenched mixture was warmed to room temperature then was concentrated. The resultant oil was dissolved in ether and the ethereal solution was washed with a 50% sodium potassium tartrate solution (2X) and with saturated brine (lX), was dried (anhydrous magnesium sulfate), and was concentrated to afford 0.800 g. (98.5% yield) of the oily hemiacetal 2-[5a-hydroxy-3a- (tetrahyd ropyran-2-ylo xy )-2 B-( 3 B-methyl-3a-( tetrahydropyran-Z-yloxy)-transl octenl -yl )cyclopent- 1a-yl]acetaldehyde, 'y-hemiacetal.

The oil was purified by column chromatography on silica gel (Baker Analyzed Reagent 60-200 mesh) using first benzene as eluent to remove high R, impurities then a 2:1 mixture of benzenezethyl acetate to elute the colorless, oily product weighing 0.601 g. (74.0% yield). Thin layer chromatography of the oily product on silica gel glass plates using a 4:1 mixture of benzenezethyl acetate as eluent showed a single spot having an R,= 0.10. The structure was confirmed by the virtual identity of its ir spectrum with that of the known 15-normethyl compound (see reference for Example 11).

EXAMPLE XIV To a solution of 0.985 g. (2.08 mmoles) of the bromide of Example I in 1.94 ml. of dimethyl sulfoxide was added dropwise 2.38 ml. (5.24 mmoles) of a 2.2 M sodium methylsulfinylmethide solution. To the resultant red ylide solution was added dropwise over a 20 minute period a solution of 0.375 g. (0.83 mmole) of the chromatographed hemiacetal of Example Xlll in 1.66 ml. of dimethyl sulfoxide. The solution was stirred for an additional 2.5 hours then was poured onto 50 ml. of ice water. The aqueous solution was acidified to pH 3 with 10% hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (X); the combined organic extracts were dried (anhydrous magnesium sulfate) and were concentrated to afford an oil weighing 0.987 g.

This oil was purified by column chromatography on 40 g. of silica gel (Baker Analyzed Reagent 60-200 mesh) using ethyl acetate in chloroform as eluent. After elution of higher R, impurities, 185 mg. (49.4% yield) of starting hemiacetal were recovered. Further elution afforded 90 mg. (26.9% yield based on unrecovered starting hemiacetal of the oily product I a-hydroxy-4a-(tetrahydropyran-2-yloxy)-3 B- 3 B- methyl-3 a-( tetrahydropyran-Z-yloxy )-trans- I -octenl yl -2a- 6-( tetraz0l-5 -yl )-cis-2-hexen- I -yl cyclopentane (herein called compound A). Thin layer chromatography of the oily product on silica gel glass plates using 10% methanol in methylene chloride as eluent showed a single spot having an R 0.40.

The structure of the product was confirmed by the virtual identity of its ir spectrum with that of the normethyl compound (see Example II).

The above compound A may be converted by the process of Example VI to la-hydroxy-3B-[3B-methyl- 3a-(tetrahydropyran-Z-yloxy)oct- I -yl]-2a-[6-(tetrazol-5 -yl )hex- I -yl ]-4a-(tetrahydropyran-Z-yloxy)cyclopentane, an intermediate which can be converted by the process of Example VII to Ia,4a-dihydroxy-3B- (3a-hydroxy-3B-methyloct- I -yl )-2a-[ 6-(tetrazol-5- yl )hex- I -yl]cyclopentane, 2-descarboxy-2-(tetrazol-S- yl)-l5-methyl-l 3,14-dihydro PGF or by the process of Example XIV above to 4a-(tetrahydropyran-Z-yloxy )-3B- 3 B-methyl-3 a-( tetrahydropyran-Z-yloxy )oct- I yl]-2a-[6-(tetrazol-5-yl)hex-I-yl]cyclopentanone, another important intermediate.

This last named intermediate may be converted by the process of Example XVII to 4a-hydroxy-3B-[3ahydroxy-BB-methyloct- I -yl]2a-[6-(tetrazol-5-yl )hex- I-yl]cyclopentanone, 2-descarboxy-2-(tetrazol-5-yl)- l5-methyl-I3,I4-dihydro PGE The 2-descarboxy-2-(tetrazol-S-yl I S-methyll3,l4-dihydro-PGE may be converted by the method of Example IX to 4B-[3a-hydroxy-3B-methyloct-I-yl]- 501-[6-(tetrazol-5-yl)hex- I -yl]cyclopent-2-enl -one, 2-descarboxy-2-(tetrazol-5-yl)-15-methyI-l3 l 4-dihydro PGA The 2-descarboxy-2-(tetrazol-5-yl)-l S-methyl- 13,14-dihydro-PGE may be converted by the method of Example XXIII to 2-descarboxy-2-(tetrazol-5-yl)- I S-methyl-l 3,14-dihydro PGF The important intermediate compound A may also be converted by a modified process of Example VI wherein the reaction temperature is to la-hydroxy-4a-( tetrahydropyran-2-yloxy )-3 B- 3B- methyl-3a-(tetrahydropyran-Z-yloxy)-trans- I -octen- I yl -2a-[ 6-( tetrazol-5 -yl-hexl -yl ]cyclopentane,

(herein called compound B). Compound B may be converted by the process of Example XV to 111,411- dihydroxy-3B-[3a-hydroxy-3B-methyl-trans-I octenyl]-2a-[6-(tetrazol-5-yl)-hex-I-yl]cyclopentane, 2-descarboxy-2-(tetrazol-S-yl)-IS-methyl PGF Compound B above may be converted by the process of Example XIV to 4a-(tetrahydropyran-Z-yloxy)-3B- [3B-methyl-3a-(tetrahydropyran-2-yloxy)-trans- I octen- I -yl]-2a-[6-(tetrazol-5-yl )-hex-I -yl]cyclopentanone, another important intermediate, which may be further converted by the process of Example XVII to 4a-hydroxy-3B-[ 3a-hydroxy-3B-methyl-trans-1 -octen- 1-yl]-2a- 6-(tetrazol-5-yl)-hex- 1 -yl]cyclopentanone, 2-descarboxy-2-(tetrazol-S-yl)-I5-methyl PGE The tetrazoyl analog of l5-methyl PGE may be converted by the process of Example IX to 4B-(3ahydroxy-3B-methyl-trans- I -octenl -yl )-5oz-[ 6-(tetrazol-5-yl )-hexl -yl]cyclopent-2-ene-l -one, the descarboxy-2-(tetrazoI-5-yl)-l S-methyl PGA The tetrazoyl analog of IS-methyl PGE may be converted by the process of Example XXIII to the 2- descarboxy-2-(tetrazol-5-yI)-IS-methyl PGF B EXAMPLE XV A solution of 8.0 mg. of the bis-Tl-IP ether of Example XIV in 0.40 ml. of a 65:35 mixture of acetic acid:- water was stirred at 40 for 5.0 hours then was concentrated by rotary evaporation. The crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-4) using 5% methanol in chloroform as eluent. A 3.5-mg. portion of the oily triol, Ia,4a-dihydroxy-3B- [3a-h'ydroxy-3 B-methyl-transl -octenl -yl -2a-[ 6- (tetrazol-S-yl)-cis-2-hexen-I-yl]cyclopentane was obtained.

The structure of the oily triol was substantiated by the virtual identity of its ir spectrum with that of the known IS-normethyl compound (see Example III). This compound is the 2-descarboxy-2-(tetrazol-S-yl)- IS-methyl PGF EXAMPLE XVI To a solution cooled to l5 of mg. (0.187 mmole) of the chromatographed bis-TI-IP ether of Example XIV in 2.0 ml. of acetone was added dropwise 0.1 ml. of Jones reagent. The mixture was stirred for 30 minutes in the cold then was quenched by the addition of 0.5 ml. of 2-propanol. The solution was diluted with ethyl acetate, then was washed with water (2X) and saturated brine (IX), was dried (anhydrous magnesium sulfate), and was concentrated to afford 82 mg. (78% yield) of an oily ketone. The crude oil was purified by column chromatography on silica gel (Baker Ana- Iyzed Reagent 60-200 mesh) using 10% ethyl acetate in chloroform as eluent which afforded 56 mg. (53.4% yield) of purified oily ketone 4a-(tetrahydropyran-2- yIoxy)-3B-[3B-methyl-3a-(tetrahydropyran-Z-yloxy)- trans-1 -octen- I -yl]-2a-[6-(tetrazol-5-yl)-cis-2-hexen- I-yl]cyclopentanone. Thin layer chromatography of the oily product on silica gel glass plates using 10% methanol in methylene chloride as eluent showed a single spot having an R;= 0.55.

The structure was confirmed by the virtual identity of its ir spectrum with that of the l5-normethylcompound (see Example IV).

EXAMPLE XVII A solution of 57 mg. (0.10 mmole) of the chromatographed bis-Tl-IP ether of Example XVI in 0.88 ml. of a 65:35 mixture of acetic acidzwater was stirred at 42 for 4.0 hours then was concentrated by rotary evaporation. Chromatography of the crude product weighing 48 mg. on silica gel (Mallinckrodt CC-4) using 2% methanol in chloroform as eluent afforded I3 mg. (33.4% yield) of oily 4a-hydroxy3B-[3a-hydroxy-3B- methyl-trans-l -octen- I -yl]-2a-[6-(tetrazol-5-yl)-cis-2- hexen-I-yl]cyclopentanone. This compound is the 2- descarboxy-Z-(tetrazol-S-yl I S-methyl PGE 23 The structure was substantiated by the practical identity of its ir spectrum to that of the l-normethyl compound. Treatment of a methanolic solution of the oily product with 40% aqueous potassium hydroxide afforded the expected uv absorption 278 mp. (6 20,000).

The tetrazoyl analog of lS-methyl PGE may be converted by the process of Example IX to 4,8-(304- hydroxy-3B-methyl-transl -octenl -yl )-5a-[6-(tetrazol-5 -yl)-cis-2-hexen-l -yl]cyclopent-2-ene- I -one, the 2-descarboxy-2-(tetrazol-S-yl)-lS-methyl PGA The tetrazoyl analog of l5-methyl PGE may be converted by the process of Example XXIII to the 2- descarboxy-2-(tetrazol-5-yl)-lS-methyl PGF EXAMPLE XVIII A mixture of the chromatographed bis-THP ether of Example II (130 mg., 0.23 mmole), 5% palladium on carbon (32.5 mg.), and methanol (13 ml.) is stirred magnetically under one atmosphere of hydrogen at to C. for 3.0 hours. The resulting mixture is filtered through Celite 545, and the filtrate is concentrated (ca. 3040, aspirator pressure) to afford the colorless, oily la-hydroxy-4a-(tetrahydropyran-2-yloxy)-3B-[ 3a-(tetrahydropyran-Z-yloxy)-transl -octenl yl -2a- 6-(tetrazol-5 -yl )-hexl -yl cyclopentane (herein called Compound C).

This compound C may be converted by the process of Example III to 3B-(3a-hydroxy-trans-l-octen-l-yl)- 2a-[6-(tetrazol-5-yl )hexl -yl]cyclopentan- 1 a,4a-diol, the 2-descarboxy-2-(tetrazol-S-yl) PGF la Compound C above may also be converted by the processes of Examples IV and V to 4a-hydroxy-3B- (3a-hydroxy-transl -octenl -yl )-2a-[6-(tetrazol-5- yl)hex-l-yl]cyclopentanone, the 2-descarboxy-2-(tet razol-S-yl) PGE The tetrazoyl analog of PGE may be converted by the process of Example IX to 4B-(3a-hydroxy-trans-locten- 1 -yl )-5a-[6-(tetrazol-5-yl )hexl -yl]cyclopent-2- en-l-one, the 2-descarboxy-2-(tetrazol-S-yl) PGA,.

The tetrazoyl analog of PGE may be converted by the process of Example XXIII to the 2-descarboxy-2- (tetrazol-5-yl)PGF EXAMPLE XIX A mixture of the known 2-[5a-hydroxy-3a(tetrahydropyran-2-yloxy)-2B-( 3a-(tetrahydropyran-Z-yloxy trans-l-octen-l-yl)-cyclopentan-la-yl]acetic acid, 7- lactone (0.840 g., 1.92 mmoles), 5% palladium on carbon (0.10 g.) and absolute ethanol ml.) is stirred magnetically under 1 atmosphere of hydrogen at room temperature for 5 hours. The resulting mixture is filtered, and the filtrate is concentrated to afford a thick, colorless oil, 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2,B-( 3a-( tetrahydropyran-Z-yloxy)octl yl)cyclopentan-la-yl]acetic acid, 'y-lactone. The compound is converted by the method of Example XIII to 2-[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy)-2B-(3a- (tetrahydropyran-Z-yloxy)oct-1-yl)cyclopentan-layl]acetaldehyde, 'y-hemiacetal.

This compound is converted by the method of Example II to 3B-[3a-(tetrahydropyran-Z-yloxy)oct-l-yl]- 2a-[6-( tetrazol-S-yl )-cis-2-hexenl -yl]-4a-(tetrahydropyran-2-yloxy)cyclopentanol (herein called compound D).

Compound D may be converted by the process of Example III to 3B-(3a-hydroxyoct-l-yl)-2a-[6-(tetrazol-S -yl)-cis-2-hexenl -yl]cyclopentan-l a,4a-diol,

the 2-descarboxy-2-(tetrazol-5-yl)-l 3 l 4-dihydro PGF Compound D may be converted by the process of Examples IV and V to 4a-hydroxy-3B-(3a-hydroxyoctl-yl )-2a- 6-(tetrazol-5-yl )-cis-2-hexenl -yl]-cyclopentanone, 2-descarboxy-2-(tetrazol-S-yl l 3 l 4-dihydro PGE The tetrazoyl analog of l3,l4-dihydro PGE may be converted by the process of Example IX to 4B-(3ahydroxyoct- 1 -yl)-5 a-[6-(tetrazol-5-yl )-cis-2-hexenl yl ]cyclopent-2-en- 1 -one, the 2-descarboxy-2-(tetrazol- 5-yl)- l 3 ,1 4-dihydro PGA The tetrazoyl analog of l3,l4-dihydro PGE may be converted by the process of Example XXIII to the 2- descarboxy-2-(tetrazol-5-yl)-l3,14-dihydro PGF EXAMPLE XX A mixture of 2.68 g. (6.00 mmoles) of the 'y-lactone starting material of Example X and 0.636 g. of 10% palladium on carbon in 29 ml. of absolute ethanol was stirred under 1 atmosphere of hydrogen at ambient temperature for 5 hours, then the mixture was filtered through Celite 545. Concentration of the filtrate afforded the desired 2-[3a-p-biphenylcarboxy-5ahydroxy-2B-[ 3-oxooctl -yl]cyclopentl a-yl]acetic acid, 'y-lactone.

This compound may be converted by the process of Example X to 2-[3a-p-biphenylcarboxy-5a-hydroxy- 2B-[3a-hydroxy-3B-methyloct-lyl]cyclopent-1a-yl1acetic acid, 'y-lactone, which may be converted by the process of Example XI to 2-[3a,5a-dihydroxy-2,B-(3ahydroxy-3B-methyloctl -yl )cyclopentl a-yl ]acetic acid, 'y-lactone.

The latter compound may be converted by the process of Example XII to 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B-( 3B-methyl-3a-(tetrahydropyran-2- yloxy)octl -yl )cyclopentanl a-yl]acetic acid, 'y-lactone which may be converted by the process of Example XIII to 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy )-2B-( 3 B-methyl-3a-( tetrahydropyran-Z-yloxy )octl yl)cyclopentl a-yl] acetaldehyde, 'y-hemiacetal.

The latter compound may be converted by the process of Example XIV to la-hydroxy-4a-(tetrahydropyran-2-yloxy)-3B-[3B-methyl-3a-(tetrahydropyran-2- yloxy)-oct-l -yl]-2a-[ 6-(tetrazol-S-yl)-cis-2-hexen-l yl]cyclopentane (herein called compound E), an important intermediate in the synthesis of 13,14-dihydrol5-lower alkyl tetrazoyl analogs of prostaglandins.

Compound E is converted by the process of Example XV to la,4a-dihydroxy-3 ,B- 3 a-hydroxy- 3 B- methyloct-l-yl]-2a-[6-(tetrazol-S-yl)-cis-2-hexen-1- yl]-cyclopentane, the 2-descarboxy-2-(tetrazol-S-yl)- 13,14-dihydro-l5-methyl PGF Compound E above may be converted by the process of Example XVI to 4a-(tetrahydropyran-Z-yloxy)-3B- [3B-methyl-3a-(tetrahydropyran-Z-yloxy )octl -yl]-2a- [6-(tetrazol-5-yl)-cis-2-hexenl -yl]cyclopentanone, an intermediate, which may be further converted by the process of Example XVII to 4a-hydroxy-3B[3ahydroxy-3 fi-methyloctl -yl]-2a-[6-(tetrazol-5-yl)-cis- 2-hexen-l-yl]-cyclopentanone, the 2-descarboxy-2- (tetrazol-5-y1)-l3 l 4-dihydrol S-methyl PGE The latter prostaglandin analog may be converted by the process of Example IX to 4B-[3a-hydroxy-3B- methyloctl -yl]-5a-[6-( tetrazol-S-yl)-cis-2-hexen-l yl]cyclopent-Z-en-l-one, the 2-descarboxy-2-(tetrazol- 5-yl)-l 3,l4-dihydro-l S-methyl PGA The lS-methyl PGE analog may be converted by the process of Example XXIII to the 2-descarboxy-2-(tetrazol- -yl)-13,l4-dihydro-lS-methyl PGF EXAMPLE XXI The known compound 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2B-(3a-(tetrahydropyran-Z-yloxy) cis-S-trans-l-octadien-1-yl)cyclopent-1a-yl] acetaldehyde, 'y-hemiacetal (see E. J. Corey,et al., J. Amer. Chem. Soc., 93, 1490 (1971) may be converted by the process of Example XI to la-hydroxy-3B-[3a-(tetrahydropyran-2-yloxy)-trans- I -cis-5-octadienl -yl]-2a-[6- (tetrazol-S -yl) cis-2-hexenl -yl ]-4a-( tetrahydropyran- 2-yloxy)cyclopentane, an important intermediate in the synthesis of tetrazoyl analogs of the PG, series, herein called compound F.

Compound'F may be, converted by the process of Example III to 3/3-(3a-hydroxy-trans-1-cis-5-octadienl-yl )-2a- 6-( tetrazol-S -yl)-cis-2-hexene-1-yl]-cyclopentan-la,4a-diol, the 2-descarb0xy-2-(tetrazol-5-yl) PGF Compound F above may be converted by the process of Example IV to 4a-(tetrahydropyran-2-yloxy)-3B- [3a-( tetrahydropyran-Z-yloxy )-transl -cis-5-octadienl-yl]cyclopentanone, an intermediate which may be converted by the process of Example V to 4a-hydroxy- 3 B-( Ba-hydroxy-trans- 1 -cis-5 -octadienl -yl )-2a- 6- (tetrazol-S-yl) cis-2-hexen-l-yl]cyclopentanone, 2-descarb0xy-2-(tetrazol-5-yl) PGE The latter prostaglandin analog may be converted by the process of Example IX to 4B-(3a-hydroxy-trans-lcis-S -octadien-l -yl )-5 a- 6-(tetrazol-5 -yl-cis-2-hexenl-yl]cyclopent-2-en- 1 -one, the 2-descarboxy-2-(tetrazol-S-yl) PGA EXAMPLE XXII To a solution of 58 mg (0.154 mmole) of the 2- descarboxy-2-(tetrazol-5-yl)PGE prepared in Example V in 5 ml. of ethyl acetate was added dropwise a solution of diazomethane in ether (ca. 0.3 ml prepared from N-methyl-N'-nitro-N-nitrosoguanidine according to the procedure found in 'Fieser and Fieser, Reagents for Organic Synthesis", Volume I, page l92)..The yellow solution was stirred for 5 minutes then was concentrated by rotary evaporation to afford a clear tan oil. Purification of the crude product by column chromatography (Baker Analyzed silica gel 60-200 mesh) using mixtures of methanol in chloroform afforded 29 mg. of 2-descarboxy-2-(2-N-methyltetrazol-5-yl)PGE and 7 mg. of 2-descarboxy-2-( l-N-methyltetrazol-S- yl)PGE The ir spectra (CHCI of both products were superimposable exhibiting strong absorbances at 1740 cm (C 0) and 965 cm (trans olefin).

The uv spectra (EtOI-I) of both products after treatment with KOH showed a k at 278 nm with an e 23,500.

the

EXAMPLE XXIII To a solution, cooled in ice, of 35 mg of the 2-descarboxy-2-(tetrazol-5-yl)PGE prepared in Example V in 7 ml. of absolute methanol was added an ice-chilled solution of 105 mg. of sodium borohydride in 12 ml. of absolute methanol. The solution was stirred under nitrogen for 20 minutes at O-5f. then for 1.0 hour at room temperature. The reaction mixture was then cooled in ice, 2 ml. of water was added, and the resul- 25 2-descarboxy-Z-(tetrazol-S-yl)-13 l 4-dihydro- .tant solution was concentrate. The concentrated mixmixtures of methanol in methylene chloride as eluents to afford first yl)PGF then 2-descarboxy-2-(tetrazol-S- 2-descarboxy-2-(tetrazol-S- as viscous, colorless oils. The ir spectra (CI-ICI of the two products were superimposable.

EXAMPLE XXIV A heterogeneous mixture of 2.24 g. (5.0 mmoles) of the known (E. .1. Corey, et al., JACS, 93, 1491 (1971) 2-[5a-hydroxy-3oz-p-phenylbenzoyloxy-ZB-(3B- hydroxy-trans-octen-l-yl)cyclopent-1a-yl]acetic acid, y-lactone and 0.680 g (5.0 mmoles) of anhydrous potassium carbonate in 22 ml. of absolute methanol was stirred at room temperature under nitrogen for 2.0 hours. The reaction mixture was then cooled in ice and was quenched by the addition of 10 ml. of 1.0N aqueous hydrochloric acid. The quenched mixture was diluted with water (22 ml.) and filtered to remove the precipitated methyl p-phenylbenzoate. The filtrate was extracted with ethyl acetate (3 X 5 ml.); the combined organic extracts were washed with saturated sodium bicarbonate and saturated brine, were dried (anhydrous magnesium sulfate), and were concentrated to afford the desired 2-[3a,5a-dihydroxy-2B-(3B- hydroxy-trans- 1 -octenl -yl )cyclopent- 1 oz-yl ]acetic acid, 'y-lactone as a viscous oil weighing 1.17 g. (87.4% yield). The ir and nmr spectra of the product were superimposable on those of the known lSa-epimer.

The starting material above may be reduced by the procedure of Example XXXII to the 2-[2B-(3B- hydroxy-transl -octen- 1 -yl )-3a,5 a-dihydroxycyclopent- 1 a-yl ]acetaldehyde, 'y-hemiacetal.

This material may be converted by the procedure of Example XXXIII to the l5-epi-2-descarboxy-2-( tetrazol-S-yl) PGF The starting material above may be hydrogenated according to the procedure of Example XXXIV to the 2-[ 3a-p-phenylbenzoyloxy-2B-( 3 B-hydroxyoctl -yl Sa-hydroxycyclopentl a-yl]acetic acid, 'y-lactone.

This compound may be reduced as described in Example XXXII to 2-[3a,5a-dihydroxy-2B-(3B-hydroxyoct- 1 -yl )cyclopentl a-yl -acetaldehyde cetal.

This compound may be converted to 15 -epi-2- descarboxy-2-(tetrazol-5 -yl )-l 3 ,14-dihydro PGF following the method of Example XXXIII.

EXAMPLE XXV y-hem ia- 27 (tetrahydropyran-2 yloxy )-trans-octenl yl )cyclopent- 1a-y1]acetic acid, y-lactone as a viscous oil weighting 2.10 g. (y 100% yield). The ir and nmr spectra were superimposable on those of the known ISa-epimer.

EXAMPLE XXVI A heterogeneous mixture of 2.02 g. of the 2-[ Sa-hydroxy-Sa-(tetrahydropyran-Z-yloxy)-2B-( 3B- (tetrahydropyran-Z-yloxy)-trans-1-octen-lyl)cyclopent-la-yl]acetic acid, 'y-lactone prepared above and 202 mg. of 5% palladium on carbon in 20 ml. of absolute methanol is stirred under 1 atmosphere of hydrogen for 4.5 hours at room temperature. The mixture is then filtered (Celite); concentration of the filtrate provides the desired 2-[5a-hydroxy-3a-(tetrahydropyran- 2-yloxy)-2B-(3/3-(tetrahydropyran-Z-yloxy)oct-1-yl)- cyclopent-1a-yl]acetic acid, 'y-lactone.

This compound may be reduced as follows in Example XXVll to provide the hemiacetal useful for the preparation of the -epi-13,14-dihydro PGE PGF a, P6P and PGA tetrazole analogs.

EXAMPLE XXVlI To a solution, cooled to 78 under nitrogen, of 1.90 g. (4.37 mmoles) the 2-[5a-hydroxy-3a-(tetrahydropyran-Z-yloxy )-2B-( 3 B-( tetrahydropyran-Z-yloxy )-transocten-l-yl)cyclopent-la-yl]-acetic acid, 'y-lactone prepared above in Example XXVI in 25 ml. of dry toluene was added dropwise 5.92 ml. of a solution of diisobutylaluminum hydride in hexane (Alfa Inorganics). The reaction was stirred for 45 minutes at 78 then was quenched by the dropwise addition of methanol until gas evolution ceased. The quenched reaction was let warm to room temperature, was diluted with ether, was washed with a 50% sodium potassium tartrate solution and with saturated brine, was dried (anhydrous magnesium sulfate), and was concentrated to provide a viscous, yellow oil which was purified by column chromatography (Baker Silica Gel 60-200 mesh) using mixtures of benzenezethyl acetate as eluents. After removal of less polar impurities the desired 2-[ 5a-hydroxy-3a-( tetrahydropyran-Z-yloxy)-2B-( 3B -(tetrahydropyran-2-yloxy)-trans-octen-1-yl)cyclopent-la-yl]acetaldehyde, 'y-hemiacetal was collected as a colorless oil weighing 1.59 g. (83.5% yield). The ir and nmr spectra were superimposable on those of the known ISa-epimer.

This compound may be converted into the 15-epi2- descarboxy-2-(tetrazol-S-yl) PGE PGF PGF PGA PGE PGF PGF, PGA,, 13,14-dihydro PGE,, PGF PGF and PGA,.

EXAMPLE XXVIII Dimethyl 2-Oxo-undecylphosphonate A solution of 49.6 g. (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml. dry tetrahydrofuran is cooled to 78 in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml. of 2.34 M n-butyllithium in hexane solution (Alfa lnorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above 65. After an additional 5 minutes stirring at 78, 36.3 g. (0.20 mole) methyl decanoate is added dropwise at a rate that kept the reaction temperature less than 70 (20 minutes). After 1.0 hour at 78 the reaction mixture is allowed to warm to ambient temperature, neutralized with ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H O), dried (MgSO and concentrated (water aspirator) to a crude residue and distilled, to give dimethyl 2-oxoundecylphosphonate.

This compound may be converted by methods both known (see: E. J. Corey, et al., J. Am. Chem. S0c., 92, 397 (1970) and described herein to the 2-descarboxy- 2-(tetrazol-5-yl)-w-tetrahomo PGE PGF PGF PGA PGE PGF PGF PGA 13,14-dihydro PGE 13,14-dihydro PGF 13,14-dihydro PGF 13,14-dihydro PGA 13,14- dihydro PGE 13,14-dihydro PGF 13,14-dihydro PGF 13,14-dihydro PGA the corresponding 14- epimers, and l5-lower alkyl analogs.

EXAMPLE XXIX Dimethyl 2-Oxo-3,3dimethylheptylphosphonate A solution of 18.4 g. (0.1 16 moles) dimethyl methylphosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to 78 in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 67.3 ml. of 1.90 M n-butyllithium in hexane solution (Alfa lnorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above 65. After an additional 5 minutes stirring at 78, 10.2 g. (58.1 mmoles) methyl 2,2-dimethylhexanoate is added dropwise at a rate that kept the reaction temperature less than (20 minutes). After 1.0 hour at 7 8 the reaction mixture is allowed to warm to ambient temperature, neutralized with 10 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in ml. water, the aqueous phase extracted with ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H O), dried (MgSO and concentrated (water aspirator) to a crude residue and distilled (b.p. 8085 at 0.05 mm) to give dimethyl 2-oxo-3,S-dimethylheptylphosphonate.

This compound may be converted by methods both known (see: E. .1. Corey, et al., J. Am. Chem. Soc., 92, 397 (1970) and described herein to the 2-descarboxy- 2-(tetrazol-5-yl)-l6,l6-dimethyl-PGE PGF PGF ,PGA PGE PGF FGF PGA 13,14- dihydro PGE 13,14-dihydro PGF 13,14-dihydro PGF 13,14-dihydro PGA 13,14-dihydro PGE 13,14-dihydro PGF 13,14-dihydro PGF 13,14-dihydro PGA the corresponding 15-epimers, and 15-lower alkyl analogs.

EXAMPLE XXX To a solution of 76 mg. (0.2 mmole) of the 2-descarboxy-2-(tetrazol-5-yl)PGF prepared in Example 111 in 1.0 ml. of pyridine is added mg. (1.0 mmole) of pivaloyl chloride. The solution is stirred for 5 hours at 45 under nitrogen then is cooled to room temperature. To the solution is then added 36 mg. (2.0 mmoles) of water. The solution is then stirred at room temperature for 2.0 hours, then is diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (3x), with water (1x), and with saturated brine (1x), is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the crude residue by silica gel chromatography provides the desired 901,1 la,l5a-trispivaloyloxy-2-descarboxy-2-(tetrazol-S-yl)PGF To a solution of 37 mg. (0.1 mmole) of 2- descarboxy-2-(tetrazol-5-yl)PGE prepared in Example V in 0.5 ml. of dry tetrahydrofuran is added 29 mg. (0.33 mmole) of formic acetic anhydride and 35 mg. (0.33 mmoles) of 2,6-lutidine. The solution is stirred for 4 hours under nitrogen at room temperature then 36 mg. (2.0 mmoles) of water is added. The mixture is stirred at room temperature for an additional 1.0 hour then is diluted with ethyl acetate. The diluted solution is washed with 0.1 N hydrochloric acid (1x), with water (1x), and with saturated brine (1x), is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the crude residue by silica gel chromatography affords the l la,labis-formyl-2-descarboxy 2-(tetrazol- 5-yl)PGE EXAMPLE XXX 2-[ 2B-( 3a-hydroxy-trans- 1 octen- 1 -yl)-3a,5a-dihydroxycyclopent-1a-yl]acetaldehyde, 'y-hemiacetal To a solution cooled to 78 of 866 mg. (1.93 mmoles) of the known 2-[3a-p-phenylbenzoyloxy-5ahydroxy-2B-(3a-hydroxytrans-l-octen-l-yl)cyclopent-1a-yl]acetic acid, 'y-lactone in 12 ml. of toluene was added 4.82 ml. (3.88 mmoles) of a 0.805 M solution of diisobutylaluminum hydride in hexane. The reaction was stirred in the cold under nitrogen for 30 minutes then was quenched by the addition of methanol (0.5 ml.). The reaction was let warm to room temperature then was concentrated to a white semisolid. The semisolid was slurried with methanol (3x), was filtered through Celite 545, and was concentrated. Purification of the crude product by silica gel chromatography using mixtures of chloroform:ethyl acetate as eluents afforded the desired 2-[2/3-(3a hydroxy-trans-l-octen-l-yl)-3a,5adihydroxycyclopent-la-yl]acetaldehyde, 'y-hemiacetal as a colorless oil weighing 304 mg. (59.5% yield).

The ir spectrum (CHCl of the product exhibited strong adsorptions at 970 cm (trans olefin) and 3380 cm (OH). The nmr spectrum (CDCl showed multiplets at 5.64-5.20 8 (2H) for the trans olefin, at 4.66-4.22 8 (1H) for the O-Cfl-O, at 4.18-3.19 8 (3H) for the OCLI, and at 2.62-0.40 8 (201-1) for the remaining protons.

EXAMPLE XXXlIl 3a,5a-dihydroxy-2B-(3a-hydroxy-trans-1-octen-1-yl)- la-[o-(tetrazol-S-yl)-cis-2-hexen-1-yl]cyclopentane To a solution 2.91 g. (6.25 mmoles) of [4-(tetrazol- 5-yl)-n-butyl]triphenylphosphonium bromide in 3 ml. of dimethyl sulfoxide is added 6.00 ml. (12.0 mmoles) of a 2.0 M solution of sodium methylsulfinylmethide in dimethyl sulfoxide. The resultant red ylide solution is stirred for minutes then a solution of 338 mg. (1.25 mmoles) of the trio] of Example XXXll in 2.0 ml. of dimethyl sulfoxide is added dropwise. The mixture is stirred at room temperature under nitrogen for 4 hours then is poured onto a mixture of ethyl acetate icewater. The aqueous layer is acidified with 10% aqueous hydrochloric acid and is extracted with ethyl acetate; the combined organic extracts are washed with water and saturated brine, are dried (anhydrous magnesium sulfate), and concentrated. Purification of the crude product by silica gel chromatography provides the desired 3a,5a-dihydroxy-2B-(3a-hydroxy-trans-l-octen- 1-yl)-1a-[7- .(tetr'azol-5-yl)-cis-2-hepten-1-yl]cyclopentane. This compound is 2-descarboxy-2-(tetrazol- 5-yl)PGF EXAMPLE XXXIV 2- 3a-p-phenylbenzoyloxy-2B-( 3a-hydroxyoctl -yl Sa-hydroxycyclopentl oz-yl]acetic acid, 'y-lactone A heterogeneous mixture of 954 mg. (2.14 mmoles) of the known 2-[3a-p-phenylbenzoyloxy-Sa-hydroxy- 2B-( 3a-hydroxy-trans-1 octenl yl )cyclopentl a-yl ]acetic acid, 'y-hemiacetal and mg. of 10% palladium on carbon in 10 ml. of absolute methanol is stirred under one atmosphere of hydrogen at room temperature for 4.5 hours. The mixture is then filtered through a pad of Celite and concentrated to afford the desired 2-[3a-p-phenylbenzoyloxy- 2B-( 3 a-hydroxyoct-1-yl)-5a-hydroxy-cyclopentla-yl]acetic acid, 'y-lactone.

.This compound may be reduced as described in Example XXXII to 2-[3a,5a-dihydroxy-2B-(3a-hydroxyoct- 1 -yl)cyclopent- 1 a-yl] acetaldehyde, 'y-hemiacetal..

This compound may be converted to 2-descarboxy-2- (tetrazol-5-yl)-l3,14-dihydro PGF following the method of Example XXXlII.

EXAMPLE XXXV 5a-hydroxy-ZB-benzyloxymethyl-3a-(tetrahydropyran- 2-yloxy)- 1 a- [6-(tetrazol-5-yl)-cisl -hexen- 1 -yl]cyclopentane To a solution of 7.06 g. (15.0 mmoles) of [4-(tetrazol-S-yl)-butyl]triphenylphosphonium bromide in 14 ml. of dimethyl sulfoxide is added dropwise 15.0 ml. of a 2.0 M solution of sodium methylsulfinylmethide in dimethyl sulfoxide. To the resultant red ylide solution is added dropwise a solution of 1.76 g. (5.0 mmoles) of the known 2-[2B-benzyloxymethyl-3a-(tetrahydropyran-2-yloxy)-5ahydroxycyclopent-1a-yl]acetaldehyde,

'y-hemiacetal in 17 ml. of dimethyl sulfoxide. After being stirred for 12 hours under nitrogen at room temperature the reaction is poured onto ice-water. The aqueous solution is overlaid with ethyl acetate, is acidified to pH 3 with 10% aqueous hydrochloric acid, and is extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried (anhydrous magnesium sulfate), and concentrated. Purification of the crude product by silica gel chromatography provides the desired 5ahydroxy-2B-benzyloxymethyl- 3a-(tetrahydropyran-Z-yloxy)-la cis-l hexen-l -yl]cyclopentane.

EXAMPLE XXXVI 5a-acetoxy-ZB-benzyloxymethyl-3a-(tetrahydropyran-2-yloxy)- l a- [6-(tetrazol-5-yl)-cis-lhexon-l-yl]cyclopentane A mixture of 1.66 g. (3.45 mmoles) of the chromatographed alcohol of Example XXXV, 5.0 ml. of pyridine and 0.736 ml. (7.78 mmoles) of acetic anhydride is stirred under nitrogen at 50 for 18 hours. The mixture is then cooled to room temperature and diluted with ethyl acetate. The organic solution is washed with 10% hydrochloric acid then water, is dried (anhydrous magnesium sulfate), and is concentrated. Purification of the crude product by silica gel chromatography provides the desired 5a-acetoxy-2B-benzyloxymethyl-3a- (tetrahydropyran-2-yloxy)-la-[6-(tetrazol-5-yl)-cis-lhexen-1-yl]cyclopentane.

3 1 EXAMPLE xxxvn a-acetoxy-2B-hydroxymethyl-3a-( tetrahydropyran-2- yloxy)-1a-[6-(tetrazol-5-yl)-hexl -yl]cyclopentane A heterogeneous mixture of 1.62 g. (3.14 mmoles) of the chromatographed benzyl ether of Example XXXVI, 324 mg. of 5% palladium on carbon, and 16.2 ml. of a 20:1 mixture of absolute ethanolzglacial acetic acid is stirred at room temperature under one atmosphere of hydrogen for 8 hours. The mixture is then filtered through Celite 545 and the filtrate is concentrated and is azeotroped under reduced pressure with toluene. Purification of the crude product by silica gel chromatography affords the desired Sa-acetoxy-ZB- hydroxymethyl-3a-(tetrahydropyran-Z-yloxy)-l a-[6- (tetrazol-S -yl )-hexl -yl]cyclopentane.

EXAMPLE XXXVIII 5a-acetoxy-2B-formyl-3a-(tetrahydropyran-2-yloxy)- 1 a-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane To a mechanically stirred solution of 3.37 ml. (41.7 mmoles) of pyridine in 50 ml. of methylene chloride, cooled to 10 to under nitrogen, is added portionwise over a period of 30 minutes 1.89 g. (18.9 mmoles) of chromium trioxide. The dark burgundy solution is let warm to room temperature then is cooled to 0. To the cold solution is added a solution of 1.01 g. (2.37 mmoles) of the alcohol of Example XXXVII in 7.0 ml. of methylene chloride with the concomitant formation of a dense black precipitate. The suspension is stirred in the cold for 15 minutes then 7.21 g. (52.2 mmoles) of finely ground sodium bisulfite monohydrate is added. After being stirred for 10 minutes 6.52 g. (52.2 mmoles) of anhydrous magnesium sulfate is added. After being stirred for 5 minutes the dark suspension is filtered through a pad of Celite, is washed with methylene chloride, then is concentrated to afford the desired 5a-acetoxy-2B-formyl-3a-(tetrahydropyran-Z-yloxy)- 1a-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane which is used without purification.

EXAMPLE XXXIX 5 a-acetoxy-2B-( 3-oxo-trans- 1 -octenl -yl)-3a-( tetrahydropyran-2- yloxy)-1a-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane To a suspension of 220 mg. (5.22 mmoles) of a 57.0% dispersion of sodium hydride in mineral oil in 40 ml. of 1,2-dimethoxyethane is added 1.16 g. (5.22 mmoles) of dimethyl-2-oxoheptylphosphonate. The mixture is stirred at room temperature for 1 hour under nitrogen with the concomitant formation of a dense white precipitate. To this suspension is added a solution of 1.13 g. (2.37 mmoles) of the aldehyde of Example EXAMPLE XL 5a-acetoxy-2B-(3a-hydroxy-trans-1 -octen-1 -yl)-3a- (tetrahydropyran- 2-yloxy)-1a-[6-(tetrazol-5-yl)-hexl -yl]cyclopentane To a solution, cooled to -78", of 852 mg. (2.0 mmoles) of the enone of Example XXXIX in 20 ml. of tetrahydrofuran is added 16 ml. (4.0 mmoles) ofa 0.25 M solution of lithium tri-sec butylborohydride in tetrahydrofuran. The solution is stirred at 78 under nitrogen for 1.0 hour then is quenched by the addition of 10 ml. of 40% aqueous acetic acid. The quenched reaction mixture is let warm to room temperature and is extracted with ethyl acetate; the combined organic extracts are washed with water and saturated brine, are dried (anhydrous magnesium sulfate), are concentrated, and azeotroped with toluene. Purification of the crude product by silica gel chromatography provides the 5a-acetoxy-2B-( 3 a-hydroxy-trans-1-octen-1-yl)- (tetrahydropyran-Z-ylo xy 1 a- 6-( tetrazol-S -yl )-hexl-yl]cyclopentane and the 5a-acetoxy-2B-(3B- hydroxy-trans- 1 -octenl -yl )-3a- (tetrahydropyran-Z-yloxy l a-[6-(tetrazol-5 -yl)hex-l -yl]cyclopentane.

The 5a-acetoxy-2B-(3B-hydroxy-trans-1-octen-1-yl)- (tetrahydropyran-Z-yloxy)-1a-[6-(tetrazol-5-yl)hex-lyl]cyclopentane may be converted by the procedures in Examples XLI to XLIX to l5-epi-2-descarboxy-2- (tetrazol-5-yl)PGE and PGF EXAMPLE XLI 5a-hydroxy-2fi-(Ba-hydroxy-trans-l -octen-1-yl)-3 a- (tetrahydropyran- 2-yloxy l a-[6-(tetrazol-5-yl )-hex- 1 -yl ]cyclopentane A mixture of 522 mg. (1.00 mmole) of the THP ether of Example XL, 3.0 ml. (3.0 mmoles) of 1.0 N aqueous sodium hydroxide, 3.0 ml. of tetrahydrofuran, and 3.0 ml. of absolute methanol is stirred under nitrogen at room temperature for 1.5 hours. The solution is then acidified by the addition of 3.0 ml. of 1.0 N hydrochloric acid and is extracted with ethyl acetate. The combined extracts are dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude prodnot by silica gel chromatography affords the desired 5a-hydroxy-2B-(3a-hydroxytrans-1-octen-l-yl)-3 a-(tetrahydropyran-2yloxy)- l a- [6-(tetrazol-5-yl)-hex-l -yl]cyclopentane.

EXAMPLE XLlI 5 a-hydroxy-2B-( 3 a-hydroxy-transl -octenl -yl )-3ahydroxy-la-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane A solution of 500 mg. of the THP ether of Example XLI in 5 ml. of a 65:35 mixture of glacial acetic acid:- water is stirred at room temperature under nitrogen for 18 hours then is concentrated and azeotroped under reduced pressure with toluene. Purification of the crude product by silica gel chromatography gives the desired 5a-hydroxy-2B-(3a-hydroxy-trans-1 -octen-l yl)-3a-hydroxy-1a-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane.

EXAMPLE XLllI 5a-acetoxy-2B-( 3a-hydroxy-trans-1-octenl -yl)-3ahydroxy-1a-[6-(tetrazol-5-yl)-hex-l -yl]cyclopentane A solution of 1.13 g. (2.16 mmoles) of the THP ether of Example XXXIX in 11 ml. of a 65:35 mixture of acetic acidzwater is stirred at room temperature under 33 nitrogen for 18 hours then is concentrated and azeotroped under reduced pressure with toluene. Purification of the crude product by silica gel chromatography provides the desired a-acetoxy-2B-(3a-hydroxy-trans- 1 octen- 1 -yl)-3a-hydroxy- 1 oz-[6-(tetrazol-5-yl)-hex- 1 yllcyclopentane.

EXAMPLE XLIV 5a-hydroxy-2B-( 3a-hydroxy-trans- 1 -octen- 1 -y1)-3ahydroxy-la-[6(tetrazo1-5-y1)-hex-1-y1]cyclopentane A solution of 424 mg. (1.00 mmole) of the diol of Example XLIII, 3.0 ml. (3.0 mmoles) of 1.0 N aqueous sodium hydroxide, 3.0 ml. of tetrahydrofuran, and 3.0 ml. of absolute methanol is stirred under nitrogen at room temperature for 2.5 hours. The solution is then acidified by the addition of 3.0 ml. of 1.0 N hydrochloric acid and is extracted with ethyl acetate. The combined organic extracts are dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude product by silica gel chromatography provides the desired 5a-hydroxy-2B-(3a-hydroxy-trans- 1 octen- 1 -yl)-3a-hydroxy-1a-[6(tetrazol-5-y1)-hex-1-y1]cyclopentane.

EXAMPLE XLV 5a-acetoxy-2B-(3a-(tetrahydropyran-Z-yloxy)-trans-1- octen-1yl)-3a-(tetrahydropyran-2-yloxy)-1a-[61 (tetrazol-S -yl)hexl -yl]-cyclopentane A solution of 250 mg. of the alcohol of Example XL, 0.250 ml. of dihydropyran, 2.5 ml. of methylene chloride, and 2.5 mg. of p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for minutes. The reaction mixture is then diluted with ether, is washed with water, is dried (anhydrous magnesium sulfate), and is concentrated to provide the desired 5a-acetoxy-2B-(3a-(tetrahydropyran-Z-yloxy)- trans-1 octenl yl )3a-(tetrahydropyran-Z-yloxy)- 1 a- [6-( tetrazol-S-yl )-hexl -y1]cyclopentane.

EXAMPLE XLVI 5 a-hydroxy-2B-( 3a-( tetrahydropyran-2-y1oxy )-trans- 1-octen-1-yl)-3 a-( tetrahydropyran-Z-yloxy)- l a- 6- (tetrazol-S -yl)-hex-1-yl]cyclopentane A homogeneous solution of 0.265 g. (0.436 mmole) of the crude bis-Tl-lP ether of Example XLV, 1.30 ml. (1.30 mmoles) of a 1.0 N aqueous sodium hydroxide solution, 1.3 ml. of methanol, and 1.3 ml. of tetrahydrofuran is stirred at room temperature overnight. The reaction mixture is then quenched by the addition of 1.30 ml. (1.30 mmoles) of a 1.0 N aqueous hydrochloric acid solution and is diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concentrated. Purification of the crude product by silica gel chromatography affords the desired 5a-hydroxy-2B-(3a-(tetrahydropyran-Z-yloxy)-trans- 1 octen- 1 yl )-3a-(tetrahydropyran-Z-yloxy 1 a-[ 6- (tetrazol-5-yl)-hex-1-yl]cyclopentane.

EXAMPLE XLVII 5a-hydroxy-2B-( 3a-hydroxy-transl -octenl yl )-3 uhydroxy-la-[6-(tetrazol-5-yl)-hex-1-yl]cyclopentane A solution of 75 mg. of alcohol of Example XLVI in 1.0 ml. of a 65:35 mixture of glacial acetic acid:water is stirred under nitrogen at room temperature for hours, then is concentrated and azeotroped with toluene. Purification of the crude product by silica gel chromatography gives the desired 5a-hydroxy-2B-(3a- 34 hydroxy-trans-l-octen-l -yl)-3a-hydroxy-1a-[6-(tetrazol-S -yl)-hex-1-yl]cyclopentane.

EXAMPLE XLVlII 4a-(tetrahydropyran-2 yloxy )-2a- 6-(tetrazol-5 yl hex- 1 yl -3[3-( 3a-(tetrahydropyran-Z-yloxy )-trans- 1 octenl -y1)cyclopentanone To a solution, cooled to 23 under nitrogen, of 0.202 g. (0.371 mmole) of the alcohol of Example XLVI in 4.0 ml. of acetone is added dropwise 0.163 ml. (0.408 mmole) of Jones reagent. The reaction is stirred in the cold for 15 minutes then is quenched by the addition of 0.163 ml. of isopropyl alcohol. The quenched reaction is stirred in the cold for 5 minutes then is diluted with ethyl acetate. The organic solution is washed with water, is dried (anhydrous magnesium sulfate), and is concentrated to afford the desired 4a-(tetrahydropyran-Z-yloxy)-2a-[6-(tetrazol-5-yl)- hex-1yl]-3B-(3a-(tetrahydropyran-Z-yloxy)-trans-1 octen-l-yl)cyclopentanone which is used without purification.

EXAMPLE XLIX 4oz-hydroxy-2a-[6-(tetrazol-5-yl)-hex-1-yl]-3B-(3ahydroxy-transl octenl yl )cyclopentanone A homogeneous solution of 0.190 g. of the crude bis-THP ether of Example XLVlIl in 2.0 ml. of a 65:35 mixture of glacial acetic acidzwater is stirred under nitrogen at roomtemperature for 12 hours, then is concentrated and azeotroped with toluene. Purification of the crude product by silica gel chromatography affords the desired 4a-hydroxy-2a-[6-(tetrazol-5-y1)- hex-l yl]-3B-(3a-hydroxy-trans-1octen-l -yl)cyclopentanone.

EXAMPLE L To a suspension 275 mg. (6.53 mmoles) of a 57.0% dispersion of sodium hydride in mineral oil in 50 ml. of dry 1,2-dimethoxyethane is added 1.63 g. (6.53 mmoles) of the phosphonate of Example XXIX. The solution is stirred at room temperature for 1 hour under nitrogen, then a solution of 1.42 g. (2.96 mmoles of the aldehyde of Example XXXVIII in 6 ml. of 1,2-dimethoxyethane is added. The solution is stirred at room temperature for 2.0 hours under nitrogen then is quenched by the addition of glacial acetic acid to pH- 5 and is concentrated. Purification of the crude product by silica gel chromatography provides the desired wherein R is hydrogen or Z-tetrahydropyranyl; and R is hydrogen, alkanoyl having from 1 to 5 carbon atoms, benzoyl, p-phenylbenzoyl, or aor B-naphthoyl. 

1. A COMPOUND OF THE STRUCTURE: 